Cancer is undoubtedly a refractory and life-threatening disease, and is also a common disease worldwide, thus it is a serious global health problem. In the United States, cancer is the leading cause of death among Americans under the age of 85; and is the second leading cause of death among older Americans. According to statistics, in the United States, about 1,500 people die of cancer every day, and there are about 3,400 new cases of cancer every day; while in China, about 1.8 million people die of cancer every year, and there are about 2.6 million new cases of cancer every year, and cancer has become the first leading cause of death among Chinese.
Cancer is a disease originating from body cells, and it is a malignant tumor. Such tumor cells are extremely abnormal and undergo random and disordered divisions, thus the growth and proliferation thereof are completely out of control. Cancer cells are very aggressive, and they attack and damage surrounding tissues. They can also leave the original tumor and enter the blood or lymphatic system, so as to form new tumors in other parts of the body.
Although there have been various anticancer medicines on the market, it is still an arduous task to treat cancer effectively, thus it remains an urgent priority to continue the research and development of anti-cancer medicines with higher activities and less toxic and side effects. Interestingly, compounds of halogenated nitro and nitroso estrogen can be used for treating cancers, especially breast cancer; more interestingly, it has also been found that aromatic halogenated nitro and nitroso compounds with simple structures have very high antitumor activities, especially for breast cancer (Kun et al. U.S. Pat. No. 5,464,871). Such compounds are inhibitors of poly(ADP-ribose) polymerase (PARP) which involves in DNA damage repair. Accordingly, DNA repair can be suppressed by inhibiting poly(ADP-ribose) polymerase, so as to enhance the therapeutic effects of radiotherapy and chemotherapy on cancers (Ossovskaya et al. US 20090149397; Sherman et al. US 20090131529 and 20090123419). In fact, the aromatic nitro compound is first converted into an aromatic nitroso compound in vivo, and the latter is the active compound that inhibits tumor growth. Due to the relatively poor water-solubility at physiological pH value and the limited stability, it is difficult to predict whether aromatic nitroso compounds can reach cancer cells, while aromatic nitro compounds do not have these problems, thus they are ideal prodrugs for aromatic nitroso compounds. Among such aromatic nitro compounds, 4-iodo-3-nitrobenzamide (INBA, Code BSI-201) is a very promising anti-cancer medicine. So far, this compound has entered into Phase III clinical trial and is further assessed for its anti-cancer effects in combination with other anticancer medicines, wherein the cancer treated is a metastatic triple-negative breast cancer (mTNBC).
Since organic iodide is very sensitive to light and air, and is poor in water-solubility, it is desirable to develop an iodine-free anti-cancer medicine having higher activity and better water-solubility. The present invention provides novel benzamide derivatives with anticancer activities, which are more effective iodine-free anticancer medicines than INBA (BSI-201).